The amyloid diseases, including Alzheimer's disease, are characterized by highly insoluble fibrous protein deposits known as amyloid plaque. Although x-ray diffraction analysis of amyloid fibrils indicates the presence of oriented repeating structure, possibly similar to Pauling's antiparallel a-sheet/cross-a fibril model for Bombyx mori silk, detailed structural information of the type required to understand the sequence-dependence of amyloid formation or for structure-based drug design (such as the alignment of residues between adjacent a strands) has not been available. Alzheimer's disease (AD) is diagnosed posthumously by the presence of amyloid plaque in the brain. The amyloid protein of AD is the &4,000 Mr a-protein. Whether the formation of plaque is a cause of the symptoms of AD or merely an epiphenomenon has not been conclusively demonstrated, and is still a matter of intense debate. There is, however, strong circumstantial evidence that the plaque is at least a promoter of the disease. The results of several experiments have suggested that the C-terminal end of the a-protein is critical for plaque formation. As the culmination of several years of effort, we recently published a structural model for the amyloid fibril formed by the 9 residue C-terminal fragment (the '9mer') of the a-protein that suggests a highly-pleated antiparallel a-sheet conformation and indicates the intermolecular alignment within the sheet. The determination of the molecular conformation was based on a series of internuclear distance measurements (range and accuracy on the order of 6 and 0.4 , respectively) made along the peptide backbone by applying the rotational resonance (R2) technique to a series of doubly 13C-labeled versions of the 9 residue fragment. Modifications to the R2 technique were necessary to account for the conformational heterogeneity in the amyloid samples, which was reflected in increased inhomogeneous 13C linewidths. Intermolecular alignment was based on qualitative interpretation of intermolecular 13C-13C interactions observed during these experiments. Several issues about the structure were not resolved in the proposed model. One issue involves the conformation of the central glycylglycyl peptide bond. It was initially thought to be cis , but the results of subsequent experiments were not consistent with this result. We have performed a series of dipole/CSA orientation-sensitive experiments (both spinning (n=2 R2) and static (static-echo)) on cis and trans model compounds which demonstrated our ability to distinguish between the two conformations. Subsequent application of these techniques to the 9mer indicate the presence of a trans conformation at the central glycylglycyl peptide bond. This eliminates one of the two families of structures we initially proposed. Furthermore, during the course of this work we discovered evidence of significant dynamic processes affecting the evolution of magnetization of 13C nuclei along the peptide backbone. Experiments are ongoing in an attempt to identify the nature of this effect. A second issue involves implementing improvements to the R2 methodology that allow us to extract more, and more precise, distance information from our experimental data. As discussed previously, changes to the R2 technique (specifically, the simulation method used to extract distance information from the experimental data), were necessary to include the effects of inhomogeneous linebroadening. Uncertainties in the method by which this effect was included led to a loss of precision in the final result. Recent control experiments, which are more sensitive to the manner in which the inhomogeneous broadening is modeled, allow for more precise calibration of the technique, and hence more precise extraction of distance information. Simulations which can accurately predict the R2-recoupled dipolar evolution of many (approaching 10) spin systems are being developed to allow more precise extraction of intermolecular proximity information from the oberved intermolecular effects. Simulating the spin dynamics of many-spin systems is generally very time-consuming, and is made worse in these experiments by the need to average over both crystallite orientations (i.e. the powder average) and chemical shift dispersion (the inhomogeneous broadening). A series of approximations have been developed which reduce simulation time, and which have been shown to reproduce the results of more detailed simulations (using the equations of motion derived directly from the spin Hamiltonian) in 3- and 4- spin systems. Extension of these methods to 6-to 10- spin systems shows that the simulations are fast enough to allow for analysis of these systems; effort continues to ensure that the nature of the approximations remains valid as the # of spins is increased.